(1) Field of the Invention
The present invention relates to 15-deoxy-16-hydroxy-16-ethynyl and 16-substituted ethynyl prostaglandins, as well as the pharmaceutically acceptable, non-toxic lower alkyl esters and salts thereof, and to the intermediates and processes for producing such compounds.
(2) Background of the Invention
Prostaglandins have classically been described as chemically related 20 carbon chain hydroxy fatty acids having the basic skeleton of prostanoic acid: ##STR2##
The prostaglandins having a hydroxyl group at the C-11 position and a keto group at the C-9 position are known as the PGE series, and those having a hydroxyl group in place of the keto group are known as the PGF series and are further designated by an or suffix to indicate the configuration of the hydroxyl group at said position. The natural compounds are the .alpha.-hydroxy substituted compounds. They may contain different degrees of unsaturation in the molecule, particularly at C-5, C-13 and C-17, the unsaturation is also indicated by a suffix. Thus, for example, the PGF.sub.1 and PGE.sub.1 series refer to prostanoic acids having a trans olefin bond at the C-13 position, while the PGF.sub.2 and PGE.sub.2 series refer to prostadienoic acids having a cis-olefin bond at the C-5 position and a trans olefin bond at the C-13 position. For a review on prostaglandins and the definition of primary prostaglandins, see, for example, S. Bergstrom, Recent Progress in Hormone Research 22, pp. 153-175 (1966) and Science 157, page 382 (1967) by the same author.
The preparation of derivatives of prostanoic acid has become of great importance since the demonstration of the highly interesting range of biological and pharmacological activities of natural prostaglandins.
The great majority of these studies have focused on modification of the two side chains, or modifications of the substituents attached to the cyclopentane moiety [see for example U. Axes et al, Synthesis Vol. 1, John Wiley and Sons Inc., New York, N. Y. 1973 and P. H. Bently, Chem. Soc. Reviews 2, 29 (1973)].
The synthesis of prostaglandin analogs possessing a 3-oxa- or 11-deoxy-3-thia moiety have been described, among others in U.S. Pat. No. 3,873,607; U.S. Pat. No. 3,950,406; Netherlands Patent No. 7305222-Q; U.S. Pat. No. 3,944,593; U.S. Pat. No. 3,931,289; and U.S. Pat. No. 3,936,487.
The synthesis of several prostaglandin analogs wherein the hydroxyl group at C-15 has been removed and a hydroxyl group has been introduced at C-16 has appeared [see for example, U.S. Pat. No. 3,950,406; Prostaglandins, Vol. 10, 733 (1975); Tetrahedron Letters, No. 48, 4217 (1975)].
Recently reports have also appeared wherein the C-16 carbon bearing a hydroxyl group is substituted with a methyl group [see Pappo et al, Tetrahedron Letters, No. 4, 235 (1975); Collin et al, U.S. Pat. No. 3,965,143; and Belgium Patent No. 827,127].
Recently the synthesis of some PGE, controls has been reported. The carbinol compounds synthesized therein were reported to exhibit more specific activities than natural PGt., Kluender et al., Tetrahedron Letters No. 24, 99. 2063-2066 (1977).
The 15-deoxy-16-hydroxy-16-vinyl and 16-cyclopropyl analogs of the E, F, A, and D series have been described in U.S. Pat. No. 4,061,670, the grandparent of this application.